Respiratory diseases caused by Streptococcus pneumoniae (pneumococcus) and influenza virus infections are major public health problems worldwide. Many studies have suggested a synergistic interaction between S. pneumoniae and influenza virus in causing human diseases. It is well known that influenza virus infection of the upper respiratory tract predisposes to secondary infections caused by S. pneumoniae in humans and experimental animals. In fact, most mortality during influenza epidemics arises from secondary bacterial infections including pneumococcal infection. Therefore, unraveling this synergy by therapeutic interventions is an attractive strategy to control human diseases caused by S. pneumoniae and influenza virus infections. Although the mechanisms of this virus-bacterial synergy remain to be defined, recent studies have implicated that viral infection may promote pneumococcal infection by promoting bacterial adhesion to respiratory epithelium. Our long-term goal is to understand how this virus-pneumococcus synergy can be modulated therapeutically for effective control of pneumococcal infection. The objective of this application is to determine how viral infection promotes pneumococcal adhesion to epithelial cells. We hypothesize that viral infection promotes pneumococcal adhesion by modulating the expression of cellular receptors. We will test our hypothesis and achieve the objective of this application by pursuing the following two specific aims. Specific Aim 1: We will determine host epithelial receptors for S. pneumoniae that are induced by influenza virus. Primary human respiratory epithelial cells will be infected with influenza virus to identify virus-induced epithelial membrane proteins by proteomic approach. The virus-induced proteins will be further evaluated for potential interactions with S. pneumoniae. Specific Aim 2: We will identify bacterial surface proteins that are involved in virus-promoted adhesion by signature-tagged mutagenesis. It is our expectation that these approaches will identify novel ligand-receptor interactions required for bacterial adhesion. These results will be significant because they are expected to open up new areas for future investigation of virus-bacterial interaction in microbial pathogenesis. Furthermore, novel pneumococcal proteins and host receptors identified in this application may provide new targets for preventive interventions.